CN111989124A - Method for preparing contrast medium - Google Patents
Method for preparing contrast medium Download PDFInfo
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- CN111989124A CN111989124A CN201980026192.4A CN201980026192A CN111989124A CN 111989124 A CN111989124 A CN 111989124A CN 201980026192 A CN201980026192 A CN 201980026192A CN 111989124 A CN111989124 A CN 111989124A
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- Prior art keywords
- lanthanide
- dota
- value
- chelating agent
- gadolinium
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 239000002872 contrast media Substances 0.000 title claims abstract description 12
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229910052747 lanthanoid Inorganic materials 0.000 claims abstract description 43
- 150000002602 lanthanoids Chemical class 0.000 claims abstract description 42
- 239000002738 chelating agent Substances 0.000 claims abstract description 37
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 25
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 229960003194 meglumine Drugs 0.000 claims description 31
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 14
- 229940075613 gadolinium oxide Drugs 0.000 claims description 11
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims description 11
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 10
- -1 especially aqueous Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 238000010668 complexation reaction Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- 239000013522 chelant Substances 0.000 claims 1
- 230000007812 deficiency Effects 0.000 claims 1
- 230000002950 deficient Effects 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 13
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 4
- 229960003823 gadoteric acid Drugs 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008364 bulk solution Substances 0.000 description 2
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- VIFBVOSDYUIKIK-UHFFFAOYSA-J sodium;gadolinium(3+);2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical class [Na+].[Gd+3].[O-]C(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 VIFBVOSDYUIKIK-UHFFFAOYSA-J 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FDSYTWVNUJTPMA-UHFFFAOYSA-N 2-[3,9-bis(carboxymethyl)-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-yl]acetic acid Chemical compound C1N(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC2=CC=CC1=N2 FDSYTWVNUJTPMA-UHFFFAOYSA-N 0.000 description 1
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 description 1
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 238000012369 In process control Methods 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ORZHVTYKPFFVMG-UHFFFAOYSA-N xylenol orange Chemical compound OC(=O)CN(CC(O)=O)CC1=C(O)C(C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=C(C)C=2)=C1 ORZHVTYKPFFVMG-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
- C01F17/00—Compounds of rare earth metals
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- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Radiology & Medical Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
A process is described for the preparation of a pharmaceutical formulation containing a contrast agent comprising a complex of a lanthanide, especially gadolinium, as a contrast agent with a macrocyclic chelator, especially DOTA.
Description
Technical Field
The present invention relates to a process for the preparation of a formulation containing a complex of a macrocyclic chelator such as DOTA (1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid) with a lanthanide such as gadolinium and a further base such as L-lysine or meglumine.
The preparations which can be prepared according to the invention can be used as contrast agents, in particular for magnetic resonance ("MR"). Formulations of this type are known.
Background
For example, the formulation sold under the trade name "DOTAREM" by GUERBET (France) is known. DOTAREM contains complexes of gadolinium and DOTA as MR-contrast agents ("gadoteric acid
") and free DOTA.
Different methods are also known for the preparation of formulations containing lanthanides, in particular gadolinium, macrocyclic complexes such as DOTA (═ 1,4,7, 10-tetraazacyclododecane-N, N ', N ", N'" -tetraacetic acid), free DOTA and bases such as meglumine.
For example, WO 2009/103744A 2 and WO 2016/015066A 1 are mentioned.
The formulations obtainable according to WO 2009/103744 a2 contain DOTA as free macrocyclic chelating agent in a mol/mol-amount of between 0.002 and 0.4%.
The methods known from WO 2009/103744 a2 and from WO 2016/015066 a1 do not use lanthanides such as gadolinium and macrocyclic chelators such as DOTA in equimolar amounts, but in excess of the lanthanide or in excess of the macrocyclic chelator. A process is disclosed in WO 2009/103744 a2 in which lanthanide and macrocyclic chelating agents are used in equimolar (stoichiometric) amounts, which is not industrially applicable (WO 2009/103744 a2, page 5).
From DE 102015013939 a1 and from WO 2017/046694 a1, a process is known for the preparation of liquid pharmaceutical formulations of gadoteric acid-meglumine, comprising the following steps:
a) mixing predetermined amounts of gadolinium oxide, DOTA and meglumine in water,
b) the pH of the mixture is adjusted to a pH between 6.5 and 8.0 by adding DOTA or an acid, wherein the amount of free DOTA is in the range of 0.0002 to 0.5% and the content of free gadolinium is less than 0.02%.
However, the method known from WO 2017/046694 a1 does not exclude the presence of free gadolinium in the formulation as high as 200 ppm.
Disclosure of Invention
The object of the present invention is to provide a simple and industrially feasible process for preparing formulations which can be used as contrast agents.
This object is solved with a method comprising the steps recited in the independent claims.
Preferred and advantageous embodiments of the method according to the invention are the subject matter of the dependent claims.
Macrocyclic chelants that can be used within the scope of the present invention are advantageously selected from the following chelants: DOTA, NOTA, DO3A, BT-DO3A, HPDO3A, PCTA, DOTAGA and derivatives thereof, and DOTA is particularly preferred. The chemical formulae of these chelating agents are known and are described, for example, in WO 2007/042504, pages 20 to 23 and WO 2003/011115, pages 8 to 11.
Within the scope of the present invention, all lanthanides are considered, in particular gadolinium, europium and dysprosium, and gadolinium is preferred.
The formulations obtainable according to the invention are advantageous because of their content of free macrocyclic chelating agent, such as DOTA, in any case ensuring that the formulation does not contain, or contains at most in an amount of less than 20ppm, a lanthanide, such as gadolinium, which is free, i.e. not complexed with a macrocyclic chelating agent.
The process according to the invention is advantageous in that it can be carried out without great expense, in good yield and without disadvantageous by-products.
In particular, the process according to the invention allows, in one possible embodiment, that the process can be carried out in good yields and on an industrial scale with equimolar amounts of a lanthanide such as gadolinium and of a macrocyclic chelating agent such as DOTA in the preparation of gadoteric acid.
The lanthanide may advantageously be added in the form of an oxide, in particular as gadolinium oxide, but other possible forms of the lanthanide, in particular lanthanide salts, are also contemplated by the present invention.
Surprisingly, when the process according to the invention is carried out in embodiments in which the lanthanide, especially gadolinium, and the macrocyclic chelating agent, such as DOTA, are present in stoichiometric (equimolar) as well as non-stoichiometric amounts in the reaction charge, the complexation is carried out completely in one step (by the lanthanide, such as gadolinium, forming a complex with the macrocyclic chelating agent, such as DOTA).
This also applies to the following cases: in the reaction additive, the amounts of macrocyclic chelator and lanthanide are selected such that not all of the lanthanide is initially complexed by the macrocyclic chelator.
Furthermore, when carrying out the process according to the invention with stoichiometric (equimolar) or non-stoichiometric amounts of a lanthanide, especially gadolinium, and a macrocyclic chelating agent such as DOTA in the reaction charge, it is advantageous that the complexation (formation of a complex from the lanthanide, such as gadolinium, and the macrocyclic chelating agent, such as DOTA) takes place well at a pH in the acidic (pH <4.5), for example at a pH between 2.0 and 4.0. The complexation then proceeds rapidly and completely in the presence of a base, such as meglumine, at a pH value in the low acidic range, for example at a pH value of 4.0 to 8.0.
The process according to the invention can be carried out in different embodiments.
The percentages used in the examples and hereinafter are based on stoichiometric amounts, which results in a content of 100% of complexes of lanthanides with macrocyclic chelating agents in the end product. Thus, 100% means the theoretical weight resulting in 100% complex content in the final product.
Thus, for example, "98% DOTA" means that DOTA is present in a molar amount of 98% based on the molar amount of gadolinium (oxide) used. Similarly, for example, "99.8% meglumine" means that meglumine is present in a molar amount of 99.8% based on the molar amount of gadolinium (oxide) used.
In a preferred embodiment according to the invention, the preparation of the pharmaceutical formulation, in particular the step of complexing the lanthanide with the macrocyclic chelating agent, is particularly advantageously carried out by adjusting the pH during the preparation process if the proportions of the raw materials used are correctly chosen.
It has been shown that insufficient amounts of lanthanide (e.g. in the form of gadolinium oxide) make preparation with pH adjustment difficult, and that an excessive lack of lanthanide makes preparation almost impossible successfully.
In a preferred embodiment, the process according to the invention, i.e. the preparation of complexes from lanthanides with macrocyclic chelating agents, in particular gadolinium-DOTA complexes (gadoteric acid), has the advantage that even in the case of different quantitative ratios (substoichiometric to superstoichiometric ratios) of the starting materials, it is possible to carry out in good yields by pH adjustment.
The preparation of formulations which can be used commercially successfully and are therefore effective and can be carried out with good results in practice (for example the preparation of the complex gadolinium-DOTA using the process according to the invention) can lead to well reproducible results with the following exemplary quantitative ratios:
-gadolinium oxide: 100 percent
-DOTA: 95 to 100%, wherein the range of 97 to 98% is preferred
-meglumine: 99.5 to 100%, with a range of 99.7 to 99.8% being preferred.
With a starting amount of 100% lanthanide (e.g. in the form of gadolinium oxide), it has been found to be advantageous in the case of the process according to the invention for the ratio DOTA to meglumine to be in the range from 98 to 99.8%.
Surprisingly, in carrying out the process according to the invention it has been shown that in embodiments of the preparation controlled by adjusting the pH in the reaction mixture it is advantageous to select the amount of meglumine such that the meglumine is substoichiometric with respect to the lanthanide (e.g. in the gadolinium oxide form), but has a stoichiometric excess of about 2% with respect to the macrocyclic chelating agent (e.g. DOTA).
Examples of formulations according to the invention for the preparation of liquids containing complexes of lanthanides (e.g. gadolinium) with macrocyclic chelators (e.g. DOTA) as MR contrast agents are described below:
To prepare a liquid pharmaceutical formulation containing a complex of a macrocyclic chelator and a lanthanide and a free macrocyclic chelator, a solution containing the chelator and the lanthanide is agitated so that the lanthanide is complexed by the macrocyclic chelator. The amount of chelating agent and the amount of lanthanide are in this case chosen such that not all of the lanthanide is complexed (a superstoichiometric amount of lanthanide). Meglumine is added to the solution to adjust the pH.
The pH of the mixture was adjusted to a pH below 5.5 by addition of DOTA.
In a further step, the pH of the solution is adjusted to 6.8 to 7.5 with a base, preferably with meglumine.
In the resulting formulation, the mol/mol amount of the free-available chelating agent (e.g., DOTA) is in the range of 0.001 to 0.5%.
In the case of an (optimal) 1:1 ratio of gadolinium to meglumine in solution, the required fraction of free DOAT is present when a pH of 5.0 to 5.5 is reached by pH-controlled addition of DOTA. The ratio can be checked with the aid of an indicator reaction. Thus, at the end of the preparation, most (preferably) rapid tests can be used. This may be an indicator reaction.
The indicator reaction can proceed as follows, wherein the conclusion of the indicator reaction is only meaningful below a solution pH of 5.5:
To 0.1ml of the sample from the reaction mixture was spiked 80. mu.l of xylenol orange indicator solution and 40ml of water. If the solution is pink, it indicates that equilibrium has not been reached in the reaction. The pH in the reaction mixture is lowered to a lower pH by the fraction of meglumine to reach the desired fraction of free DOTA.
The method according to the invention is advantageous in that:
very simple large-scale industrial processes.
Easy and fast process control.
Preparation by targeted adjustment of the pH without costly in-process control.
The preparation can be carried out in a vessel.
The problem of technical difficulties such as the water content of the raw material, or the presence of possible free gadolinium in the range of more than 20ppm, is solved, thus guaranteeing a higher product safety.
The preparation of gadoteric acid-containing bulk solutions on an industrial scale, described in the figures, is illustrated in more detail below
The steps of example (a):
the preparation of the bulk solution was carried out in a class C clean room.
Before the preparation of the total solution starts, the further parts of the required instruments and filling are preferably autoclaved (autoklaviert) at more than 121 ℃ for at least 30 minutes. To prepare the total solution, a defined amount of water for injection is introduced into the reaction vessel and a temperature above 70 ℃, preferably between 70 ℃ and 80 ℃, is set.
Step 1:
water for injection is provided and the temperature of the water for injection is adjusted to 70 ℃ to 80 ℃.
Step 2:
add 97% DOTA based on water free material.
And step 3:
100% gadolinium oxide, based on pure substance, is added. The reaction mixture (solution) was stirred.
And 4, step 4:
99.8% of meglumine, based on the theoretical amount used, are added.
And 5:
DOTA was added until the pH of the solution was less than 5.5. In particular, the pH should be between 4.5 and 5.0, preferably between 4.6 and 4.8.
Step 6:
DOTA is added, if desired (optionally), in an amount of 500 to 700ppm, preferably 700ppm, calculated on the basis of the final concentration of the complex in the finished pharmaceutical formulation.
And 7:
the pH is adjusted with meglumine to a value between 7.0 and 7.5.
And 8:
the final volume was adjusted with water for injection.
The final total solution is filtered, in particular the solution can be sterile filtered and subsequently filled in bottles with the corresponding filling volume.
The bottles were closed immediately after filling and terminally sterilized in an autoclave.
Examples
Examples of the method according to the invention are given below:
example 1: amount of DOTA: 97.0%, meglumine amount: 99.8 percent
104.22g DOTA (corrected for initial weight and calculated as 97.0% based on water content) was dissolved in about 300ml of water having a temperature of 75 ℃ to 80 ℃. 45.59g gadolinium oxide (initial weight corrected for purity) is added and the addition is stirred at least 75 ℃ for at least one hour. 48.71g of meglumine are then incorporated into the solution and stirred at least 75 ℃ for at least one hour. The pH of the solution was about 7. The pH of the solution is adjusted to about 6 (e.g., pH 6.3) by adding a defined amount of DOTA. A small amount of DOTA is admixed to the solution with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After a pH of 4.9 was reached, also a DOTA corresponding to 660ppm was added to the solution. The pH of 4.4 was then adjusted to 7.1 with meglumine. The reaction batch was filled to a total volume of 500ml, filtered and autoclaved.
Example 2: amount of DOTA: 98.0%, meglumine amount: 99.7 percent
106.20g DOTA (initial weight corrected for water content and calculated as 98.0%) was dissolved in about 300ml of water having a temperature of 75 ℃ to 80 ℃. 45.59g gadolinium oxide (initial weight corrected for purity) is added and the addition is stirred at least 75 ℃ for at least one hour. 48.66g of meglumine are then incorporated into the solution and stirred at least 75 ℃ for at least one hour. The pH of the solution was about 7. The pH of the solution was adjusted to about 6(pH 6.1) by adding a defined amount of DOTA. A small amount of DOTA is admixed to the solution with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After a pH of 4.4 was reached, also DOTA corresponding to 620ppm was added to the solution. The pH of 3.9 was then adjusted to 7.1 with meglumine. The reaction batch was filled to a total volume of 500ml, filtered and autoclaved.
Example 3: amount of DOTA: 98.0%, meglumine amount: 99.5 percent
106.20g DOTA (initial weight corrected for water content and calculated as 98.0%) was dissolved in about 300ml of water having a temperature of 75 ℃ to 80 ℃. 45.59g gadolinium oxide (initial weight corrected for purity) is added and the addition is stirred at least 75 ℃ for at least one hour. The solution was then spiked with 48.56g of meglumine and stirred at least 75 ℃ for at least one hour. The pH of the solution was about 7. The pH of the solution was adjusted to about 6(pH 5.9) by adding a defined amount of DOTA. A small amount of DOTA is admixed to the solution with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After a pH of 4.7 was reached, DOTA corresponding to 910ppm was also added to the solution. The pH of 4.1 was then adjusted to 7.1 with meglumine. The reaction batch was filled to a total volume of 500ml, filtered and autoclaved.
The above-described indicator reaction can be assisted in all cases to determine the proportions of DOTA and meglumine and to check the equilibrium in the solution, so that fluctuations in the initial share of the three raw materials (mixed in the batch vessel) can be tracked well.
As demonstrated in the examples, in the process according to the invention, the final content of excess DOTA can be adjusted to about 200 to 2000 ppm.
In the case of industrial quantities, filling to the total volume is a step in which, in the case of well-defined starting quantities, the adjustment of the final volume generally requires only a small change, thereby eliminating a subsequent adjustment of the amount of DOTA.
In the case of laboratory scale, corresponding adjustments can be made prior to the high-pressure treatment, if desired.
In summary, embodiments of the invention may be described as follows:
a process is described for the preparation of a pharmaceutical formulation containing a contrast agent comprising a complex of a lanthanide, especially gadolinium, as a contrast agent with a macrocyclic chelator, especially DOTA.
Claims (14)
1. Process for the preparation of a liquid, especially aqueous, formulation containing a complex of a lanthanide and a macrocyclic chelating agent as a contrast agent, especially as a contrast agent for magnetic resonance, wherein the formulation does not contain a macrocyclic chelating agent, characterized by the following successive process steps:
a) the macrocyclic chelant is dissolved in the water,
b) the addition of a lanthanide to the reaction mixture,
c) adding an alkali into the mixture, and adding the alkali into the mixture,
d) the complexation of the lanthanide with the macrocyclic chelating agent is carried out, preferably in the presence of a base, at a pH higher than 5.5, in particular at a pH between 6.5 and 8.0,
e) Adjusting the pH value of the solution obtained after step d) to a value below 5.0,
f) adjusting the pH to a value above 6.5, preferably above 7.0, in particular to a pH between 7.0 and 7.5, and
g) diluting the solution obtained after step g) to a predetermined final volume.
2. The method according to claim 1, characterized in that gadolinium is used as lanthanide.
3. The method according to claim 1 or 2, characterized in that the lanthanide is used in the form of an oxide, in particular gadolinium in the form of gadolinium oxide.
4. A process according to any one of claims 1 to 3, characterized in that DOTA is used as macrocyclic chelating agent.
5. The process according to any one of claims 1 to 4, characterized in that an organic base, preferably meglumine, is added in step c).
6. The process according to claim 5, characterized in that in step c) a base, preferably meglumine, is added in an insufficient amount based on the lanthanide used, such as gadolinium.
7. Process according to any one of claims 1 to 6, characterized in that DOTA is used for adjusting the pH value in step e), wherein preferably a pH value of between 4.5 and 5.5, in particular a value of between 4.6 and 4.7, is adjusted.
8. The method according to any one of claims 1 to 7, characterized in that the pH value in step f) is adjusted to a value between 6.5 and 8.0, in particular to a value between 6.8 and 7.5, preferably to a value between 6.9 and 7.3.
9. The process according to any one of claims 1 to 8, characterized in that the adjustment of the pH value in step f) is carried out with a base, in particular with meglumine.
10. The method according to any one of claims 1 to 9, characterized in that the lanthanide and the macrocyclic chelating agent are used in different or in the same molar amount with respect to each other.
11. The method according to claim 10, characterized in that the macrocyclic chelating agent, preferably DOTA, is used in a deficient amount based on the lanthanide used, such as gadolinium.
12. The process according to any one of claims 1 to 11, characterized in that a chelating agent, especially DOTA, is added after step e), especially up to a content of 500 to 799 ppm.
13. Process according to any one of claims 1 to 12, characterized in that the base, in particular meglumine, is present in a stoichiometric deficiency based on the lanthanide used and in a stoichiometric excess based on the macrocyclic chelating agent used.
14. The process according to any one of claims 1 to 13, characterized in that the lanthanide is present in stoichiometric excess based on the macrocyclic chelating agent when carrying out step d) of claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ATA50162/2018 | 2018-02-23 | ||
| ATA50162/2018A AT521001B1 (en) | 2018-02-23 | 2018-02-23 | Manufacturing process for a contrast agent |
| PCT/EP2019/054190 WO2019162313A1 (en) | 2018-02-23 | 2019-02-20 | Process for producing a contrast agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111989124A true CN111989124A (en) | 2020-11-24 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980026192.4A Pending CN111989124A (en) | 2018-02-23 | 2019-02-20 | Method for preparing contrast medium |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20200390910A1 (en) |
| EP (1) | EP3755382A1 (en) |
| CN (1) | CN111989124A (en) |
| AT (1) | AT521001B1 (en) |
| WO (1) | WO2019162313A1 (en) |
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| US9458117B2 (en) * | 2013-01-28 | 2016-10-04 | Agfa Healthcare Nv | Process for producing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and complexes thereof |
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2018
- 2018-02-23 AT ATA50162/2018A patent/AT521001B1/en active
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2019
- 2019-02-20 EP EP19706593.1A patent/EP3755382A1/en active Pending
- 2019-02-20 WO PCT/EP2019/054190 patent/WO2019162313A1/en unknown
- 2019-02-20 CN CN201980026192.4A patent/CN111989124A/en active Pending
- 2019-02-20 US US16/971,734 patent/US20200390910A1/en active Pending
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| US5876695A (en) * | 1986-11-28 | 1999-03-02 | Schering Aktiengesellschaft | Metal complex-containing pharmaceutical agents |
| US6083479A (en) * | 1997-09-26 | 2000-07-04 | Schering Aktiengesellschaft | Contrast media for infarction and necrosis imaging |
| CN101977633A (en) * | 2008-02-19 | 2011-02-16 | 法国加柏公司 | Process for preparing a pharmaceutical formulation of contrast agents |
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Also Published As
| Publication number | Publication date |
|---|---|
| AT521001B1 (en) | 2020-10-15 |
| WO2019162313A1 (en) | 2019-08-29 |
| EP3755382A1 (en) | 2020-12-30 |
| AT521001A1 (en) | 2019-09-15 |
| US20200390910A1 (en) | 2020-12-17 |
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